In order to understand the causes of diseases such as cancer, kidney disease, heart failure, diabetes, or degenerative diseases of the nervous system, it is important to define small macromolecular assembly/organization and their position, their spatial and temporal dynamics, along with the capability of studying these events as it happens in living cells. These capabilities are critical for understanding cellular processes and changes in cellular structures associated with disease and developmental abnormalities. Toward this goal, we are most interested in Super-resolution approaches to deliver information on subcellular organization at different timescales using various labeling probes. For example, the N-STORM imaging system will provide the necessary capacity to determine the interaction of cancer cells with other cell types, including lymphocytes and vascular cells that form blood vessels, as well as circulating inflammatory cells in the vasculature during cancer progression in the translational animal models. Our BVAMC investigators study mutations in proteins that affect the function of non-motile cilia that exist in renal epithelial cells in polycystic kidney disease (PKD). Conventional confocal microscopy does not have the resolution to provide detailed information and to define structural and functional relationships in cilia and to examine ciliary defects that lead to PKD. The N-STORM super-resolution microscope overcomes the resolution limits posed by wavelength of light in conventional microscopy and would be an outstanding tool to explore, at the micron to nanometer level, primary cilia. Heart failure investigators are studying how several types of immune cells, including regulatory T- lymphocytes, interact with the injured and failing myocardium. Super resolution microscopy will permit more precise characterization of immune cell-cardiomyocyte interactions, cell migration, extravasation, and cell biology related to receptor trafficking, cell polarization, proliferation in live cell models. This technology will allow BVAMC investigators to efficiently employ fluorescent techniques for detecting protein-protein interactions in living cells with high precision to obtain detailed insight that will enable better design of receptor antagonist drug(s). With super-resolution microscopy, BVAMC investigators focusing on HIV can directly address in living cells critical questions involving HIV envelope (Env) protein biosynthesis, including post- translational modification, and importantly, solutions to critical problems that currently limit the production of native-like HIV-1 Env vaccine immunogens. Finally, the N-STORM will provide live cell imaging to track the cellular uptake and intracellular path of highly destruction proteases in cardiac myocytes and lung epithelial cells and facilitate development of targeted therapies in inflammatory diseases and autoimmune diseases. These studies represent a cross-section of diverse areas of disease oriented, clinically relevant research of the BVAMC investigators. The application of this exciting new technology will enhance funding capabilities and most importantly our research goals and mission of Veteran-centric medical care.